ES2931301T3 - Pharmaceutical composition comprising HMG-CoA reductase inhibitors and fenofibrate - Google Patents

Abstract

The present invention provides a multilayer pharmaceutical composition comprising a fixed dose combination of rosuvastatin or a pharmaceutically acceptable salt thereof and fenofibrate or a pharmaceutically acceptable salt thereof, wherein fenofibrate or a pharmaceutically acceptable salt and rosuvastatin or a pharmaceutically acceptable salt pharmaceutically acceptable are present in separate layers, namely a fenofibrate layer and a rosuvastatin layer, where fenofibrate and rosuvastatin are immediately released from the fenofibrate layer and rosuvastatin layer, respectively, and where the fenofibrate layer comprises micronized fenofibrate. Furthermore, the present invention provides a process for the preparation of said composition. (Automatic translation with Google Translate, without legal value)

Description

DESCRIPTION

Pharmaceutical composition comprising HMG-CoA reductase inhibitors and fenofibrate

field of invention

The present invention provides a multilayer pharmaceutical composition comprising a fixed dose combination of rosuvastatin or a pharmaceutically acceptable salt thereof and fenofibrate or a pharmaceutically acceptable salt thereof, wherein fenofibrate or a pharmaceutically acceptable salt and rosuvastatin or a pharmaceutically acceptable salt pharmaceutically acceptable are present in separate layers, namely, a fenofibrate layer and a rosuvastatin layer, where fenofibrate and rosuvastatin are immediately released from the fenofibrate layer and rosuvastatin layer, respectively, and where the fenofibrate comprises micronized fenofibrate. Furthermore, the present invention provides a process for the preparation of said composition.

Background of the invention

Rosuvastatin is a selective and competitive inhibitor of the HMG-CoA reductase inhibitor and has lipid-lowering activity. The chemical name of rosuvastatin is bis[(E)-7-[4(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]-pyrimidin-5-yl](3R,5S)- acid 3,5dihydroxyhept-6-enoic]. Rosuvastatin corresponds to the compound with the following structure (Formula I):

Rosuvastatin is known, for example, from US RE37 314 E and EP 0521 471 B1. Both prior art documents disclose that rosuvastatin is especially effective as an inhibitor of HMG-CoA reductase. In addition, rosuvastatin calcium is marketed as a single-drug formulation under the name CRESTOR® in the form of 5-mg tablets; 10mg; 20mg and 40mg. CRESTOR® has two approved therapeutic indications, namely the treatment of hypercholesterolemia in adults, adolescents and children from 6 years of age and the prevention of cardiovascular accidents.

The treatment of hypercholesterolemia is a long-term treatment that may comprise a first initial phase of oral treatment followed by a second phase of dose adjustment. In particular, the recommended starting dose is 5 or 10 mg once daily, followed by a titration change to 20 or 40 mg, which can be done, if necessary, after 4 weeks of treatment. For the prevention of cardiovascular accidents, the dose used is 20 mg.

After oral administration, rosuvastatin undergoes limited metabolism. In vitro metabolism studies with human hepatocytes indicate that rosuvastatin is an inappropriate substrate for cytochrome P450-based metabolism.

The document EP 2306982 B1 aims to improve the dissolution profile of CRESTOR®. To this end, it discloses a pharmaceutical composition in which calcium rosuvastatin is provided together with an alkali metal carbonate, bicarbonate or a mixture thereof. The molar ratio of these components is 1:0.43-1.75 (rosuvastatin calcium: alkali metal carbonate or bicarbonate or a mixture thereof). This composition is reported to have a beneficial dissolution profile of rosuvastatin calcium in 0.1 N HCl medium provided that the anhydrous form of sodium carbonate is present in a range of 0.5% to 2% by weight of the composition. pharmaceutical. The pharmaceutical composition is preferably an oral dosage form such as a tablet or another oral dosage form such as a capsule, a granule, a mini-tablet or the like.

Fenofibrate is an activator of peroxisome proliferator-activated receptor alpha (PPARa). Through activation of PPARα, fenofibrate increases lipolysis and the clearance of triglyceride-rich atherogenic particles from plasma by activating lipoprotein lipase and reducing the production of apoprotein CIII. PPARa activation also induces an increase in the synthesis of apoproteins AI and AII. From a chemical point of view, fenofibrate is 2-[4-(4-chlorobenzoyl)phenoxy]-2-methyl-propanoic acid 1-methylethyl ester and has the following structure (Formula II):

Fenofibrate is disclosed in GB 1415295 A. Furthermore, fenofibrate is commercially available and marketed as a single drug formulation in different pharmaceutical forms and strengths, for example, as TRICOR® in the form of 54 mg and 160 mg tablets; as SUPRALIP® in the UK or as s EcALIP SUPRA® in Spain in the form of 160 mg tablets; and as LIPANTHYL® in the form of 200 mg capsules.

In the case of SUPRALIP®/SECALIP SUPRA® 160 mg tablets, it is indicated for the treatment of severe hypertriglyceridaemia with or without low HDL cholesterol, for mixed hyperlipidaemia when statins are not tolerated, as well as for the treatment of Mixed hyperlipidemia in patients with high cardiovascular risk. The recommended dose for these indications is one tablet containing fenofibrate 160 mg once daily. Following oral administration, fenofibrate is rapidly hydrolyzed to esterases of the active metabolite, fenofibric acid. Fenofibric acid is primarily conjugated with glucuronic acid and then excreted in the urine. Document US 6277405 B1 refers to a process for preparing a composition with a supposedly improved fenofibrate solution compared to some of the commercially available products. The procedure comprises the steps of: (a) preparing a suspension of fenofibrate in micronized form with a particle size of less than 20 pm, in a solution of hydrophilic polymer and, optionally, a surfactant, (b) applying the suspension from step ( a) to an inert water-soluble vehicle. The disclosed composition allegedly exhibits a fenofibrate dissolution of at least 75% in 30 minutes, measured using the 75 rpm rotary paddle method according to Ph. Eur. in a dissolution medium consisting of water and 2% by weight of polysorbate 80 or a dissolution medium consisting of water and 0.025 M sodium lauryl sulfate.

Document US 2011/0 311 625 A1 discloses that the solubility of an active pharmaceutical ingredient influences the bioavailability of a drug. Furthermore, it teaches that fenofibrate is a sparingly soluble drug. Due to its low water solubility, fenofibrate poses the problem of low dissolution. It is poorly absorbed from the digestive tract and consequently its bioavailability is considered to be incomplete and irregular. Poor dissolution properties are said to be alleviated by providing the fenofibrate in a specific form, namely, in the form of a tablet comprising a core and a shell surrounding the core, wherein the shell surrounding the core comprises the fenofibrate, a hydrophilic polymer and a hydrophilic carrier.

The document EP 0330 532 B1 proposes a new therapeutic composition containing fenofibrate that has been comicnized with a solid surfactant. The new composition is claimed to have improved fenofibrate dissolution and therefore greater bioavailability. The daily dose of the drug can be reduced from 300 mg to 200 mg and from 100 mg to 67 mg without having to make compromises in therapeutic efficacy.

Instead of single drug formulations, some prior art references suggest the combined use of fenofibrate and an HMG-CoA inhibitor. This should be the most effective means of controlling cholesterol and lipids. In fact, fenofibrate treatment is often prescribed in conjunction with a statin, as clinicians seem to prefer the use of, for example, fenofibrate due to its triglyceride-lowering and HDL-C-raising effects, while using a statin. HMG-CoA inhibitor for its positive effects on lowering LDL-C and increasing HDL-C and/or related diseases. Fixed dose combinations including a fibrate and a statin as active pharmaceutical ingredients are known from the following documents.

EP 1 185 274 B1, for example, discloses a combination of the HMG-CoA reductase inhibitor rosuvastatin with an inducer, inhibitor or substrate of the P450 isoenzyme 3A4 for simultaneous, separate or sequential use in therapy.

WO 2005/034908 A2 discloses pharmaceutical compositions comprising a combination of a fibrate and a statin and a common carrier. The vehicle is selected from the group consisting of a hydrophobic, hydrophilic, and water-miscible vehicle. At least 80% w/w, but preferably 99.9% w/w of the total amount of fibrate and statin (active substance) is dissolved in the common vehicle. However, from a technical point of view, it is difficult to achieve such a solution. Fenofibrate and statin should be dissolved in a mixture of PEG 6000 and Poloxamer 188 (70:30) or glyceryl monostearate at 70°C and the solution subsequently sprayed onto lactose in a fluid bed. Furthermore, the fenofibrate release characteristics of said composition are insufficient.

Document EP 1 853 249 A2 discloses a pharmaceutical composition comprising at least two active pharmaceutical ingredients, namely fenofibrate as the first ingredient and an HMG-CoA reductase inhibitor or a derived from it as a second principle. It provides a single solid dosage form for oral administration comprising a solid fenofibrate composition and a solid HMG-CoA reductase inhibitor composition, preferably a statin composition, the active ingredients being present as separate entities. The document discloses that the fibrate that is contained in the composition is present in the form of a solid solution. According to the disclosed examples, the fenofibrate granules were prepared in a rather laborious manner, namely according to the method described in WO 2005/034 920 A1. Again, this means that the fenofibrate must be dissolved in a solution of polyethylene glycol 6000 and poloxamer 188 (70:30 w/w ratio) at 75°C and the homogeneous solution subsequently sprayed onto lactose. In addition to this drawback, the fenofibrate dissolution profile of the disclosed pharmaceutical composition is also unsatisfactory due to the separation of the active substances into two entities.

WO 2008/075320 A2 discloses a process for preparing an oral pharmaceutical composition comprising fenofibrate alone or in combination with at least one other antilipidemic agent in a single dosage form that can conveniently be administered once or twice daily. The document discloses a process for preparing an oral pharmaceutical composition comprising fenofibrate, wherein the process comprises the steps of preparing a solution comprising fenofibrate, a surfactant and a hydrophilic polymer, and spraying the solution onto one or more inert carriers, to prepare granules. This document also requires the preparation of the fenofibrate composition by preparing a fenofibrate solution and using the solution to prepare the granules.

Kumar et al., IJPSR, 2016; vol. 7(1): 413-23 discloses a combination of rosuvastatin calcium and fenofibrate as a bilayer tablet in which the rosuvastatin layer provides sustained release of rosuvastatin and the fenofibrate layer provides immediate release of fenofibrate.

In summary, most of the aforementioned prior art describes single drug formulations of fenofibrate and rosuvastatin. Only a few prior art documents refer to drug combinations of a fibrate and a statin in a single dosage form. Most notably, however, none of the prior art documents disclose how fenofibrate dissolution can be improved when both fenofibrate and rosuvastatin are combined in a single dosage form. Furthermore, the known fixed dose combinations are disadvantageous in terms of their manufacture. The preparation of a solid solution of the active substances introduces a high degree of complexity into the manufacturing process. To prepare such a solid solution, the manufacturer is required to use heating equipment and add certain excipients (eg PEG, poloxamers, waxes).

In addition, none of the prior art documents have been shown to be effective in improving treatment compliance by providing a fixed-dose combination of fenofibrate and rosuvastatin that is bioequivalent in vivo to a concomitant intake of SECALIP SUPRA® and CRESTOR® monotherapies. .

In view of the state of the art, there is a great need to develop a new combination product of fenofibrate and rosuvastatin that overcomes the known drawbacks of conventional state of the art compositions.

Object of the invention

Therefore, the object of the present invention is to provide a combination product of fenofibrate and rosuvastatin which can be manufactured in a simple way and which has an improved dissolution profile, at least for fenofibrate.

Summary of the invention

The inventors of the present invention have surprisingly discovered that a pharmaceutical composition comprising a fixed-dose combination of rosuvastatin and fenofibrate or their pharmaceutically acceptable salts, wherein the composition has a multilayer structure, and rosuvastatin and fenofibrate are in separate layers, and in which fenofibrate and rosuvastatin are immediately released from the fenofibrate layer and rosuvastatin layer respectively, and the fenofibrate layer comprises fenofibrate which is in the form of micronized fenofibrate, exhibits an excellent dissolution profile of fenofibrate. Preferably, the fenofibrate dissolution profile is characterized by the fact that greater than 74% of the fenofibrate content dissolves in 30 minutes when measured in a USP type II dissolution apparatus, using 1000 mL of 0. 05 M in water as dissolution medium at 37 °C and shaking at 50 revolutions per minute.

Advantageously, the compositions of the present invention can be obtained by conventional wet granulation processes, ie, unlike state of the art fixed dose combinations, they do not require the preparation of a solid solution of fenofibrate. On the other hand, the compositions of the present invention show a faster dissolution of fenofibrate than the fixed-dose combinations of the state of the art, that is, they exhibit a dissolution profile in which more than 74% by weight of the fenofibrate is released. over a period of 30 minutes when measured in a USP Type II dissolution apparatus, using 1000 mL of 0.05 M sodium lauryl sulfate in water as the dissolution medium at 37°C and shaking at 50 revolutions per minute.

The pharmaceutical composition of the invention allows, advantageously, to replicate the bioavailability in vivo of the simultaneous intake of SECALIP SUPRA® and CRESTOR® already marketed in equivalent doses. In this regard, the inventors have discovered that the total drug exposure exhibited after once daily administration of the fixed dose combination of the present invention is bioequivalent to the total drug exposure obtained after once daily co-administration. day of a 160 mg tablet of SECALIP SUPRA® and a 20 mg tablet of CRESTOR®. This means that the fixed-dose combination of the present invention exhibits comparable bioavailability pharmacokinetic parameters (eg, Cmax, Tmax, AUC ⁰ -t, AUC ⁰ -~) of fenofibric acid, the active metabolite of fenofibrate, and rosuvastatin.

Surprisingly, due to the faster in vitro dissolution profile of fenofibrate from the multilayer pharmaceutical composition of the invention compared to the monolayer pharmaceutical compositions of the state of the art, the multilayer pharmaceutical composition of the invention is capable of replicating the in vivo bioavailability of SECALIP SUPRA®.

In addition, the inventors have discovered that the multilayer pharmaceutical composition comprising a fixed-dose combination of rosuvastatin and fenofibrate, or their pharmaceutically acceptable salts, shows good stability of both active ingredients at a temperature of 40°C and a relative humidity of 75°C. % during time periods of 1 month, 2 months and 3 months.

Therefore, the multilayer pharmaceutical composition of the invention that comprises a fixed-dose combination of rosuvastatin and fenofibrate, or their pharmaceutically acceptable salts, represents a significant improvement over the corresponding monotherapies, since it provides the two active ingredients in a single tablet for treatment once a day, thus reducing the patient's pill burden. Therefore, the fixed-dose combination is suitable for patients with mixed dyslipidemia who currently need to take the two monotherapies separately, thus meeting an unmet medical need and providing an improvement in ensuring compliance and adherence to treatment. .

Brief description of the drawings

Figure 1 shows the mean plasma concentration (MPC) of fenofibrate, expressed as the mean plasma concentration of its metabolite fenofibric acid, during 96 h after oral administration of a single dose of: a) the fixed dose combination according to the present invention , in the form of the rosuvastatin and fenofibrate bilayer tablet of example 4c (test, dots represented as squares); b) the 160 mg tablet of SECALIP SUPRA® (reference, points represented as circles). CPM means mean plasma concentration (pg/ml) and T refers to time expressed in hours.

Figure 2 shows the mean plasmatic concentration (MPC) of rosuvastatin, during 96 h after oral administration of a single dose of: a) the fixed dose combination according to the present invention, in the form of a bilayer tablet of rosuvastatin and fenofibrate of the example 4c) (test, points represented as squares); b) the 20 mg tablet of CRESTOR® (reference, points represented as circles). CPM means mean plasma concentration (pg/ml) and T refers to time expressed in hours.

Detailed description of the invention

Unless otherwise indicated, terms in the present specification are intended to have their ordinary meaning in the relevant art.

The present invention relates to compositions for the treatment of cardiovascular diseases, including, but not limited to, coronary heart disease, heart failure and cardiomyopathy, congenital heart disease, atherosclerosis, ischemia/reperfusion, hypertension, restenosis, acute rheumatic fever, rheumatic heart disease, and arterial inflammation. The present invention refers to pharmaceutical formulations with a synergistic effect from the combined use of a fenofibrate with a statin. Said formulations are presented in multiple pharmaceutical forms produced by formulating the two active principles separately. The excipients used in the formulations are selected so that the interaction between them and the active agents is minimized, and the formulations are prepared accordingly. Multiple dosage forms prepared in this manner can be produced so that the two active agents can have different and/or the same release characteristics.

As mentioned above, both fenofibrate and the active agents from the group of statins have solubility/dissolution problems. It is known that it is very difficult to develop a dosage form having a high dissolution rate of a drug that hardly dissolves. However, the inventors have succeeded in producing a multilayer composition comprising rosuvastatin and fenofibrate or their pharmaceutically acceptable salts, in which the fenofibrate dissolution after 60 minutes is at least 20% higher compared to a composition comprising a monolayer. of rosuvastatin or one of its pharmaceutically acceptable salts and fenofibrate. or one of its pharmaceutically acceptable salts.

The term "rosuvastatin", as used herein, defines the molecule represented by the structural formula (I), but also pharmaceutically acceptable salts thereof. The multilayer composition of the invention comprises an amount of rosuvastatin calcium or, alternatively, an amount of another pharmaceutically acceptable salt equivalent to the amount of rosuvastatin calcium. Examples of such salts include barium salts, strontium salts, zinc salts, cesium salts, cadmium salts, magnesium salts, sodium salts, and ammonium salts.

The term "fenofibrate", as used herein, is defined as the molecule represented by structural formula (II), but also as pharmaceutically acceptable salts thereof.

The present invention provides a multilayer pharmaceutical composition comprising a fixed dose combination of rosuvastatin or a pharmaceutically acceptable salt thereof and fenofibrate or a pharmaceutically acceptable salt thereof and a process for the preparation of said multilayer composition.

In a preferred embodiment, the present invention provides a multilayer pharmaceutical composition comprising a fixed dose combination of rosuvastatin or a pharmaceutically acceptable salt thereof and fenofibrate or a pharmaceutically acceptable salt thereof, wherein the multilayer composition is a bilayer tablet. immediate release.

In another embodiment, the present invention provides a multilayer pharmaceutical composition comprising a fixed dose combination of rosuvastatin or a pharmaceutically acceptable salt thereof and fenofibrate or a pharmaceutically acceptable salt thereof, wherein fenofibrate and rosuvastatin are immediately released. of the fenofibrate layer and the rosuvastatin layer, respectively, and the fenofibrate dissolution after 60 minutes from the multi-layer composition comprising a fixed-dose combination is at least 20% higher compared to a composition comprising a monolayer of rosuvastatin or one of its pharmaceutically acceptable salts and fenofibrate or one of its pharmaceutically acceptable salts.

In another embodiment, the present invention provides a multilayer pharmaceutical composition comprising a fixed dose combination of rosuvastatin or a pharmaceutically acceptable salt thereof and fenofibrate or a pharmaceutically acceptable salt thereof, wherein fenofibrate and rosuvastatin are immediately released. of the fenofibrate layer and the rosuvastatin layer, respectively, and the fenofibrate dissolution after 60 minutes from the multi-layer composition comprising a fixed-dose combination is at least 20% higher compared to a composition comprising a monolayer of rosuvastatin or one of its pharmaceutically acceptable salts and fenofibrate or one of its pharmaceutically acceptable salts, when measured in a USP Type II dissolution apparatus, using 1000 mL of 0.05 M sodium lauryl sulfate in water as the dissolution medium at 37 °C and shaking at 50 revolutions per minute.

In another embodiment, the present invention provides a multilayer pharmaceutical composition comprising a fixed dose combination of rosuvastatin or a pharmaceutically acceptable salt thereof and fenofibrate or a pharmaceutically acceptable salt thereof, wherein fenofibrate and rosuvastatin are immediately released. of the fenofibrate layer and the rosuvastatin layer, respectively, and the fenofibrate layer comprises micronized fenofibrate, and the fenofibrate dissolution after 60 minutes from the multilayer composition comprising a fixed dose combination is at least 20% higher compared to a composition comprising a monolayer of rosuvastatin or one of its pharmaceutically acceptable salts and fenofibrate or one of its pharmaceutically acceptable salts, when measured in a type II ^u S ^p dissolution apparatus, using 1000 ml of sodium lauryl sulfate. 0.05 M sodium in water as dissolution medium at 37 °C and shaking at 50 revolutions per minute.

In another embodiment, the present invention provides a bilayer tablet comprising a fixed dose combination of rosuvastatin or a pharmaceutically acceptable salt thereof and fenofibrate or a pharmaceutically acceptable salt thereof, wherein dissolution of the fenofibrate after 60 minutes to from the bilayer tablet comprising a fixed dose the combination is at least 20% higher compared to a composition comprising a monolayer of rosuvastatin or one of its pharmaceutically acceptable salts and fenofibrate or one of its pharmaceutically acceptable salts, when measured in a USP type II dissolution apparatus, using 1000 mL of 0.05 M sodium lauryl sulfate in water as the dissolution medium at 37°C and shaking at 50 rpm.

In another embodiment, the present invention provides a multilayer pharmaceutical composition comprising a fixed dose combination of rosuvastatin or a pharmaceutically acceptable salt thereof and fenofibrate or a pharmaceutically acceptable salt thereof, wherein rosuvastatin or a pharmaceutically acceptable salt is present. in an amount of 5 mg to 50 mg, and the fenofibrate or pharmaceutically acceptable salt is present in an amount of 100 mg to 200 mg.

In a preferred embodiment, the present invention provides a bilayer tablet comprising a fixed dose combination of rosuvastatin or a pharmaceutically acceptable salt thereof and fenofibrate or a pharmaceutically acceptable salt thereof, wherein rosuvastatin or a pharmaceutically acceptable salt thereof is present in an amount of 5 mg to 20 mg, and the fenofibrate or pharmaceutically acceptable salt is present in an amount of 140 mg to 180 mg.

In another embodiment, the present invention provides a multilayer pharmaceutical composition comprising a fixed dose combination of rosuvastatin or a pharmaceutically acceptable salt thereof and fenofibrate or a pharmaceutically acceptable salt thereof, wherein (1) rosuvastatin or its salt pharmaceutically acceptable is present in an amount of 5 mg to 20 mg, and fenofibrate or its pharmaceutically acceptable salt is present in an amount of 140 mg to 180 mg and (2) rosuvastatin and fenofibrate are not mixed, (3) the fenofibrate and rosuvastatin are immediately released from the fenofibrate layer and the rosuvastatin layer, respectively, and (4) fenofibrate dissolution after 60 minutes from the multilayer composition is at least 20% greater compared to a composition that comprises a monolayer of rosuvastatin or a pharmaceutically acceptable salt thereof and fenofibrate or a pharmaceutically acceptable salt thereof, when measured in a USP Type II dissolution apparatus, using 1000 mL of 0.05 M sodium lauryl sulfate in water as the dissolution medium at 37°C and shaking at 50 rpm.

In a preferred embodiment, the present invention provides a multilayered pharmaceutical composition comprising a fixed dose combination of rosuvastatin or a pharmaceutically acceptable salt thereof and fenofibrate or a pharmaceutically acceptable salt thereof, wherein the multilayered composition comprises 5 to 20 mg rosuvastatin or a pharmaceutically acceptable salt thereof and 160 mg fenofibrate, wherein (1) rosuvastatin and fenofibrate do not mix, (2) fenofibrate and rosuvastatin are immediately released from the fenofibrate layer and the rosuvastatin layer, respectively, and (3) the fenofibrate dissolution after 15 minutes is more than 67% w/w of the total fenofibrate content and (4) the fenofibrate dissolution after 60 minutes from the multilayer composition is at least 20% higher compared to a composition comprising a monolayer of rosuvastatin or one of its pharmaceutically acceptable salts and fenofibrate or one of its pharmaceutically acceptable salts, when measured in a USP Type II dissolution apparatus, using 1000 mL of 0.05 M sodium lauryl sulfate in water as the dissolution medium at 37°C and shaking at 50 revolutions per minute.

In another embodiment, the present invention provides a bilayer tablet comprising a fixed dose combination of rosuvastatin or a pharmaceutically acceptable salt thereof and fenofibrate or a pharmaceutically acceptable salt thereof, wherein rosuvastatin or a pharmaceutically acceptable salt thereof is present. in an amount of 5 mg to 20 mg, and the fenofibrate or its pharmaceutically acceptable salt is present in an amount of 140 mg to 180 mg and wherein the dissolution of the fenofibrate after 60 minutes from the bilayer tablet is at least a 20% higher compared to a composition comprising a monolayer of rosuvastatin or a pharmaceutically acceptable salt and fenofibrate or a pharmaceutically acceptable salt, when measured in a USP Type II dissolution apparatus using 1000 mL of sodium lauryl sulfate. 0.05 M sodium in water as dissolution medium at 37 °C and shaking at 50 revolutions per minute.

In a preferred embodiment, the present invention provides a bilayer tablet comprising a fixed dose combination of rosuvastatin or a pharmaceutically acceptable salt thereof and fenofibrate or a pharmaceutically acceptable salt thereof, wherein the bilayer tablet comprises 5 to 20 mg of rosuvastatin or a pharmaceutically acceptable salt thereof and 160 mg of fenofibrate and/or wherein the dissolution of fenofibrate after 60 minutes from the bilayer tablet is at least 20% greater compared to a composition comprising a monolayer of rosuvastatin or one of its pharmaceutically acceptable salts and fenofibrate or one of its pharmaceutically acceptable salts, when measured in a USP Type II dissolution apparatus, using 1000 mL of 0.05 M sodium lauryl sulfate in water as the dissolution medium at 37 °C and shaking at 50 revolutions per minute.

In another embodiment, the present invention provides a bilayer tablet comprising a fixed dose combination of rosuvastatin or a pharmaceutically acceptable salt thereof and fenofibrate or a pharmaceutically acceptable salt thereof, wherein (1) rosuvastatin or a pharmaceutically acceptable salt thereof acceptable is present in an amount of 5 mg to 20 mg, and fenofibrate or its pharmaceutically acceptable salt is present in an amount of 140 mg to 180 mg and (2) both rosuvastatin and fenofibrate are not mixed with each other, (3 ) fenofibrate and rosuvastatin are immediately released from the fenofibrate layer and rosuvastatin layer, respectively, and/or (4) fenofibrate dissolution after 60 minutes from the bilayer tablet is at least 20% greater compared to with a composition comprising a monolayer of rosuvastatin or a pharmaceutically acceptable salt thereof and fenofibrate or a pharmaceutically acceptable salt thereof, when measured in a USP type II dissolution apparatus, using 1000 mL of 0.05 M sodium lauryl sulfate in water as the dissolution medium at 37°C and shaking at 50 rpm.

In a preferred embodiment, the present invention provides a bilayer tablet comprising a fixed dose combination of rosuvastatin or a pharmaceutically acceptable salt thereof and fenofibrate or a pharmaceutically acceptable salt thereof, wherein the bilayer tablet comprises 5 to 20 mg of rosuvastatin or its pharmaceutically acceptable salt and 160 mg of fenofibrate in which; (1) both rosuvastatin and fenofibrate do not mix with each other (ie, they do not form a monolayer), (2) fenofibrate and rosuvastatin are immediately released from the fenofibrate layer and the rosuvastatin layer, respectively, and (3) the fenofibrate dissolution after 15 minutes is more than 67% w/w of the fenofibrate content and/or (4) the fenofibrate dissolution after 60 minutes from the bilayer tablet is at least 20% greater in comparison to a composition comprising a monolayer of rosuvastatin or a pharmaceutically acceptable salt thereof and fenofibrate or a pharmaceutically acceptable salt thereof, when measured in a USP type II dissolution apparatus, using 1000 mL sodium lauryl sulfate 0.05 M in water as a dissolution medium at 37 °C and shaking at 50 revolutions per minute.

In one embodiment, the present invention provides a multilayer pharmaceutical composition comprising a fixed dose combination of rosuvastatin or a pharmaceutically acceptable salt thereof and fenofibrate or a pharmaceutically acceptable salt thereof, wherein fenofibrate and rosuvastatin are present in separate layers and in which the fenofibrate is micronized fenofibrate. In a preferred embodiment, the micronized fenofibrate has a mean volumetric diameter D(v, 50) greater than 0.02 pm and less than or equal to 20 pm, preferably greater than 0.04 pm and less than or equal to 10 pm, more preferably greater than 0.05 pm and less than or equal to 7 pm, even more preferably greater than 0.05 pm and less than or equal to 5 pm, more preferably greater than 0.05 pm and less than or equal to 4 pm.

In one embodiment, the present invention provides a multilayer pharmaceutical composition comprising a fixed dose combination of rosuvastatin or a pharmaceutically acceptable salt thereof and fenofibrate or a pharmaceutically acceptable salt thereof, wherein fenofibrate and rosuvastatin are present in separate layers and in which the fenofibrate is micronized fenofibrate and in which the fenofibrate and rosuvastatin are immediately released from the fenofibrate layer and the rosuvastatin layer, respectively. In a preferred embodiment, the micronized fenofibrate has a mean volumetric diameter D(v, 50) greater than 0.02 pm and less than or equal to 20 pm, preferably greater than 0.04 pm and less than or equal to 10 pm, more preferably greater than 0.05 pm and less than or equal to 7 pm, even more preferably greater than 0.05 pm and less than or equal to 5 pm, more preferably greater than 0.05 pm and less than or equal to 4 pm.

In one embodiment, the present invention provides a multilayer pharmaceutical composition comprising a fixed dose combination of rosuvastatin or a pharmaceutically acceptable salt thereof and fenofibrate or a pharmaceutically acceptable salt thereof, wherein fenofibrate and rosuvastatin are present in separate layers and in which the fenofibrate is micronized fenofibrate and in which the fenofibrate and rosuvastatin are immediately released from the fenofibrate layer and the rosuvastatin layer, respectively, and the fenofibrate dissolution after 60 minutes from the composition multilayer composition comprising a fixed-dose combination is at least 20% higher compared to a composition comprising a monolayer of rosuvastatin or a pharmaceutically acceptable salt thereof and fenofibrate or a pharmaceutically acceptable salt, when measured in a metering apparatus. USP type II solution, using 1000 mL of 0.05 sodium lauryl sulfate M in water as a dissolution medium at 37 °C and shaking at 50 revolutions per minute. In a preferred embodiment, the micronized fenofibrate has a mean volumetric diameter D(v, 50) greater than 0.02 pm and less than or equal to 20 pm, preferably greater than 0.04 pm and less than or equal to 10 pm, more preferably greater than 0.05 pm and less than or equal to 7 pm, even more preferably greater than 0.05 pm and less than or equal to 5 pm, more preferably greater than 0.05 pm and less than or equal to 4 pm.

In another embodiment, the micronized fenofibrate has a particle size distribution (DTP) such that D(v,10) is greater than 0.02 pm and less than or equal to 7 pm, preferably greater than 0.04 pm and less than or equal to 5 pm, more preferably greater than 0.04 pm and less than or equal to 4 pm, even more preferably greater than 0.05 pm and less than or equal to 3 pm, even more preferably greater than 0.05 pm and less than or equal to 2 pm; and/or D(v,50) is greater than 0.04 pm and less than or equal to 20 pm, preferably greater than 0.08 pm and less than or equal to 10 pm, more preferably greater than 0.1 pm and less than or equal to 7 pm, even more preferably greater than 0.1 pm and less than or equal to 5 pm, even more preferably greater than 0.1 pm and less than or equal to 4 pm; and/or D(v,90) is greater than 0.05 pm and less than or equal to 47 pm, preferably greater than 0.1 pm and less than or equal to 25 pm, more preferably greater than 0.2 pm and less than or equal to 18 pm, even more preferably greater than 0.4 pm and less than or equal to 13 pm, even more preferably greater than 0.5 pm and less than or equal to 10 pm.

The width of the particle size distribution of the micronized fenofibrate, expressed as a range, may be from 1.2 to 3, preferably from 1.3 to 2.5, more preferably from 1.6 to 2.3. According to Chew et al. J Pharm Pharmaceut Sci 2002, 5, 162-168, the "range" corresponds to the following relationship: [D(v,0,9) - D(v,0,1)]/D(v,0,5) .

The DTP parameters (D(v,0.9), D(v,0.5) and D(v,0.1)) of micronized fenofibrate are determined by measuring the characteristic equivalent sphere diameter, known as volumetric diameter, by laser diffraction.

In another embodiment, the present invention provides a multilayer pharmaceutical composition comprising a fixed dose combination of rosuvastatin or a pharmaceutically acceptable salt thereof and fenofibrate or a pharmaceutically acceptable salt thereof, wherein fenofibrate and rosuvastatin are present in separate layers, and wherein the fenofibrate is not in the form of a solid solution or a solid dispersion. In this context, the fact that the fenofibrate is not in the form of a solid solution or a solid dispersion means that the fenofibrate layer comprises less than 20% w/w or is free of an excipient or vehicle selected from the group consisting of polyethylene glycols , polypropylene glycols, polyoxyethylenes, polyoxypropylenes, poloxamers, straight-chain saturated hydrocarbons, sorbitan esters, paraffins, fats, oils and mixtures thereof and having a melting point of less than 100 °C. Preferably, the fenofibrate layer comprises less than 20% w/w or is free of excipients or carriers with a melting point below 100°C, regardless of the class of compounds from which the carriers or carriers are selected. In a preferred embodiment, the compositions of the invention comprise a fenofibrate layer that comprises less than 20% w/w or is free of an excipient or vehicle with a melting point below 75°C, preferably below 80°C, plus preferably less than 90 °C, even more preferably less than 100 °C.

In another embodiment, the present invention provides a multilayer pharmaceutical composition comprising a fixed dose combination of rosuvastatin or a pharmaceutically acceptable salt thereof and fenofibrate or a pharmaceutically acceptable salt thereof, wherein fenofibrate and rosuvastatin are present in separate layers, and in which fenofibrate and rosuvastatin are immediately released from the fenofibrate layer and rosuvastatin layer, respectively, and in which the composition exhibits a dissolution profile in which more than 74% w/dissolves wt of fenofibrate in 30 minutes, preferably greater than 77% w/w, more preferably greater than 80% w/w, even more preferably greater than 83% w/w, when measured in a USP Type II dissolution apparatus, using 1000 mL of 0.05 M sodium lauryl sulfate in water as dissolution medium at 37°C and shaking at 50 rpm.

In another embodiment, the compositions of the invention have a dissolution profile according to which: up to 48% w/w of fenofibrate dissolves in 5 minutes, from 49 to 79% w/w of fenofibrate dissolves in 10 minutes, from 65 to 95% w/w of fenofibrate dissolves in 15 minutes, from 68 to 98% w/w of fenofibrate dissolves in 20 minutes, from 74 to 100% w/w of fenofibrate dissolves in 30 minutes, from 79 to 100% w/w fenofibrate dissolves in 45 minutes, and 80 to 100% w/w fenofibrate dissolves in 60 minutes, when measured in a USP Type II dissolution apparatus, using 1000 mL sodium lauryl sulfate 0.05 M in water as dissolution medium at 37 °C and shaking at 50 revolutions per minute. In another preferred embodiment, the compositions of the invention have a dissolution profile according to which: up to 43% w/w of fenofibrate dissolves in 5 minutes, from 54 to 74% w/w of fenofibrate dissolves in 10 minutes, from 70 to 90% w/w of fenofibrate dissolves in 15 minutes, from 73 to 93% w/w of fenofibrate dissolves in 20 minutes, from 78 to 98% w/w of fenofibrate dissolves in 30 minutes, from 84 100% w/w fenofibrate dissolves in 45 minutes, and 85 to 100% w/w fenofibrate dissolves in 60 minutes, when measured in a USP Type II dissolution apparatus, using 1000 mL of sodium lauryl sulfate. 0.05 M sodium in water as dissolution medium at 37 °C and shaking at 50 revolutions per minute. In another more preferred embodiment, the compositions of the invention have a dissolution profile according to which: up to 38% w/w of fenofibrate dissolves in 5 minutes, from 59 to 69% w/w of fenofibrate dissolves in 10 minutes. , from 75 to 85% w/w of fenofibrate dissolves in 15 minutes, from 78 to 88% w/w of fenofibrate dissolves in 20 minutes, from 83 to 93% w/w of fenofibrate dissolves in 30 minutes, from 89 to 99% w/w of fenofibrate dissolves in 45 minutes, and 90 to 100% w/w of fenofibrate dissolves in 60 minutes, when measured in a USP Type II dissolution apparatus, using 1000 mL of lauryl sulfate 0.05 M sodium in water as dissolution medium at 37 °C and shaking at 50 revolutions per minute.

In another embodiment, the present invention provides a multilayer pharmaceutical composition comprising a fixed dose combination of rosuvastatin or a pharmaceutically acceptable salt thereof and fenofibrate or a pharmaceutically acceptable salt thereof, wherein fenofibrate and rosuvastatin are present in separate layers, and in which the fenofibrate and rosuvastatin are immediately released from the fenofibrate layer and the rosuvastatin layer, respectively, and in which the fenofibrate is micronized fenofibrate, and in which the fenofibrate is not in the form of a dispersion solid.

In another embodiment, the present invention provides a multilayer pharmaceutical composition comprising a fixed dose combination of rosuvastatin or a pharmaceutically acceptable salt thereof and fenofibrate or a pharmaceutically acceptable salt thereof, wherein fenofibrate and rosuvastatin are present in separate layers, and wherein the fenofibrate and rosuvastatin are immediately released from the fenofibrate layer and the rosuvastatin layer, respectively, and wherein the fenofibrate is micronized fenofibrate, wherein the fenofibrate is not in the form of a solid dispersion, and wherein the composition exhibits a dissolution profile whereby greater than 74% w/w fenofibrate dissolves in 30 minutes, when measured in a USP Type II dissolution apparatus, using 1000 mL of 0 sodium lauryl sulfate, 05 M in water as dissolution medium at 37 °C and shaking at 50 revolutions per minute.

In one embodiment, following oral administration of a single dose of the fixed-dose combination of the present invention under fed conditions, fenofibrate or a pharmaceutically acceptable salt thereof, equivalent to 160 mg fenofibrate, exhibits a maximum plasma concentration (Cmax) from 6,500 pg/ml to 12,500 pg/ml, expressed as plasma concentration of its metabolite fenofibric acid. In a preferred embodiment, after oral administration of a single dose of the fixed dose combination of the present invention under fed conditions, fenofibrate or a pharmaceutically acceptable salt thereof, equivalent to 160 mg fenofibrate, shows a plasma concentration maximum (Cmax) from 8,000 pg/ml to 11,000 pg/ml, expressed as plasma concentration of its metabolite fenofibric acid. In a more preferred embodiment, after oral administration of a single dose of the fixed dose combination of the present invention under fed conditions, fenofibrate or a pharmaceutically acceptable salt thereof, equivalent to 160 mg of fenofibrate, exhibits a concentration maximum plasma (Cmax) from 9,000 pg/ml to 10,000 pg/ml, expressed as plasma concentration of its metabolite fenofibric acid. The term Cmax refers to the maximum concentration of the fenofibric acid metabolite in the blood after oral administration of a single dose of the fixed-dose combination of the present invention under fed conditions.

In one embodiment, following oral administration of a single dose of the fixed-dose combination of the present invention under fed conditions, rosuvastatin or a pharmaceutically acceptable salt thereof, equivalent to 20 mg rosuvastatin, exhibits a plasma concentration maximum (Cmax) of 9,000 ng/ml at 29,000ng/mL. In a preferred embodiment, following oral administration of a single dose of the fixed-dose combination of the present invention under fed conditions, rosuvastatin or a pharmaceutically acceptable salt thereof, equivalent to 20 mg rosuvastatin, exhibits a concentration maximum plasma (Cmax) from 13,000 ng/ml to 23,000 ng/ml. In a more preferred embodiment, following oral administration of a single dose of the fixed-dose combination of the present invention under fed conditions, rosuvastatin or a pharmaceutically acceptable salt thereof, equivalent to 20 mg rosuvastatin, exhibits a maximum plasma concentration (Cmax) from 17,000 ng/ml to 19,000 ng/ml. The term "Cmax" refers to the maximum concentration of rosuvastatin in the blood after oral administration of a single dose of the fixed-dose combination of the present invention under fed conditions.

In one embodiment, following oral administration of a single dose of the fixed-dose combination of the present invention under fed conditions, fenofibrate or a pharmaceutically acceptable salt thereof, equivalent to 160 mg fenofibrate, exhibits a time to maximum plasma concentration (Tmax) from 1.5 h to 7 h, expressed as plasma concentration of its metabolite fenofibric acid. In a preferred embodiment, following oral administration of a single dose of the fixed dose combination of the present invention under fed conditions, fenofibrate or a pharmaceutically acceptable salt thereof, equivalent to 160 mg fenofibrate, exhibits a time to the maximum plasma concentration (Tmax) from 5 h to 6 h, expressed as the plasma concentration of its metabolite fenofibric acid. In a more preferred embodiment, following oral administration of a single dose of the fixed dose combination of the present invention under fed conditions, fenofibrate or a pharmaceutically acceptable salt thereof, equivalent to 160 mg of fenofibrate, exhibits a time to peak plasma concentration (Tmax) from 5.25 to 5.75 h, expressed as plasma concentration of its metabolite fenofibric acid. The term "Tmax" refers to the time in hours that Cmax is reached after oral administration of a single dose of the fixed dose combination of the present invention under fed conditions.

In one embodiment, following oral administration of a single dose of the fixed-dose combination of the present invention under fed conditions, rosuvastatin or a pharmaceutically acceptable salt thereof, equivalent to 20 mg rosuvastatin, exhibits a time to the maximum plasma concentration (Tmax) from 1 h to 7 h. In a preferred embodiment, following oral administration of a single dose of the fixed-dose combination of the present invention under fed conditions, rosuvastatin or a pharmaceutically acceptable salt thereof, equivalent to 20 mg rosuvastatin, exhibits a time to maximum plasma concentration (Tmax) from 4 h to 7 h. In a more preferred embodiment, following oral administration of a single dose of the fixed-dose combination of the present invention under fed conditions, rosuvastatin or a pharmaceutically acceptable salt thereof, equivalent to 20 mg rosuvastatin, exhibits a time to maximum plasma concentration (Tmax) from 5.25 h to 5.75 h. The term "Tmax" refers to the time in hours that Cmax is reached after oral administration of a single dose of the fixed dose combination of the present invention under fed conditions.

In one embodiment, following oral administration of a single dose of the fixed-dose combination of the present invention under fed conditions, fenofibrate or a pharmaceutically acceptable salt thereof, equivalent to 160 mg of fenofibrate, exhibits an area under the plasma concentration/time curve (AUC(0-t)) from time 0 to 96 hours from 80,500 pgh/mL to 310,500 pgh/mL, expressed as plasma concentration of its metabolite fenofibric acid. In a preferred embodiment, after oral administration of a single dose of the fixed-dose combination of the present invention under fed conditions, fenofibrate or a pharmaceutically acceptable salt thereof, equivalent to 160 mg fenofibrate, shows an area under the time/plasma concentration curve from time 0 to 96 hours (AUC(0-t)) from 122,500 pgh/mL to 222,500 pg hr/mL, expressed as plasma concentration of its metabolite fenofibric acid. In a more preferred embodiment, after oral administration of a single dose of the fixed dose combination of the present invention under fed conditions, fenofibrate or a pharmaceutically acceptable salt thereof, equivalent to 160 mg of fenofibrate, exhibits an area under the plasma concentration/time curve from time 0 to 96 hours (AUC(0-t)) from 147,500 pgh/mL to 197,500 pgh/mL, expressed as plasma concentration of its metabolite fenofibric acid. The term "AUC" refers to the area under the time/plasma concentration curve after oral administration of a single dose of the composition of the present invention. AUC0-infinity indicates the area under the plasma concentration vs. time curve from time 0 to infinity and AUCo-t indicates the area under the plasma concentration vs. time curve from time 0 to time t.

In one embodiment, following oral administration of a single dose of the fixed-dose combination of the present invention under fed conditions, rosuvastatin or a pharmaceutically acceptable salt thereof, equivalent to 20 mg rosuvastatin, exhibits an area under the time/plasma concentration curve from time 0 to 96 hours (AUC(0-t)) from 76,000 ngh/mL to 210,000 ngh/mL. In a preferred embodiment, after oral administration of a single dose of the fixed-dose combination of the present invention under fed conditions, rosuvastatin or a pharmaceutically acceptable salt thereof, equivalent to 20 mg rosuvastatin, shows an area under the time/plasma concentration curve from time 0 to 96 hours (AUC(0-t)) from 101,000 ng hr/mL to 171,000 ng hr/mL. In a more preferred embodiment, following oral administration of a single dose of the fixed dose combination of the present invention under fed conditions, rosuvastatin or a pharmaceutically acceptable salt thereof, equivalent to 20 mg of rosuvastatin, shows an area under the time curve/plasma concentration from time 0 to 96 hours (AUC(0-t)) of 126,000 ngh/mL to 146,000 ngh/mL. The term "AUC" refers to the area under the time/plasma concentration curve after oral administration of a single dose of the composition of the present invention. AUC0-infinity indicates the area under the plasma concentration vs. time curve from time 0 to infinity and AUCo-t indicates the area under the plasma concentration vs. time curve from time 0 to time t.

In one embodiment, following oral administration of a single dose of the fixed-dose combination of the present invention under fed conditions, fenofibrate or a pharmaceutically acceptable salt thereof, equivalent to 160 mg fenofibrate, exhibits a half-life ( T1/2) from 12 h to 40 h, expressed as plasmatic concentration of its metabolite fenofibric acid. In a preferred embodiment, following oral administration of a single dose of the fixed dose combination of the present invention under fed conditions, fenofibrate or a pharmaceutically acceptable salt thereof, equivalent to 160 mg fenofibrate, exhibits a half-life (T1/2) from 19 h to 25 h, expressed as plasma concentration of its metabolite fenofibric acid. The term "half-life (T1/2)" refers to the time required for fenofibrate to lose half of its pharmacological activity.

In one embodiment, following administration of a single oral dose of the fixed-dose combination of the present invention under fed conditions, rosuvastatin or a pharmaceutically acceptable salt thereof, equivalent to 20 mg rosuvastatin, exhibits a half-life (T1/2) from 6 a.m. to 44 p.m. In a preferred embodiment, following oral administration of a single dose of the fixed-dose combination of the present invention under fed conditions, rosuvastatin or a pharmaceutically acceptable salt thereof, equivalent to 20 mg rosuvastatin, exhibits a life of average (T1/2) from 10 a.m. to 4 p.m. The term "half-life (T1/2)" refers to the time required for rosuvastatin to lose half of its pharmacological activity.

Values of pharmacokinetic parameters after a single dose of the fixed-dose combination of the present invention under fed conditions, as mentioned above (ie, Cmax, Tmax, AUC ⁰ -t, AUC ⁰ -~) , indicate that once-daily administration of the fixed-dose combination of the present invention is bioequivalent to the total drug exposure obtained after once-daily administration of the simultaneous intake of a 160-mg tablet of SECALIP SUPRA® and a 20 mg tablet of CRESTOR®. The 90% confidence interval for the relationship of the pharmacokinetic parameters of the fixed dose combination of the present invention and the comparative composition that falls outside the scope of the present invention is within the acceptance interval of 80.00-125 .00% according to the EMA Guidelines on bioequivalence research (CPMP/EWP/QWP/1401/98 Rev. 1/ Corr, 2010).

In one embodiment, the present invention provides a multilayer pharmaceutical composition comprising a fixed dose combination of rosuvastatin or a pharmaceutically acceptable salt thereof and fenofibrate or a pharmaceutically acceptable salt thereof, wherein the fenofibrate or a pharmaceutically acceptable salt thereof itself and rosuvastatin or a pharmaceutically acceptable salt thereof are present in separate layers, and wherein fenofibrate and rosuvastatin are immediately released from the fenofibrate layer and rosuvastatin layer, respectively, and wherein impurity- Fenofibrate B is below the limit of quantification under storage conditions of 40°C and 75% relative humidity after a period of 3 months.

In one embodiment, the present invention provides a multilayer pharmaceutical composition comprising a fixed dose combination of rosuvastatin or a pharmaceutically acceptable salt thereof and fenofibrate or a pharmaceutically acceptable salt thereof, wherein the fenofibrate or a pharmaceutically acceptable salt thereof itself and rosuvastatin or a pharmaceutically acceptable salt thereof are present in separate layers, and wherein fenofibrate and rosuvastatin are immediately released from the fenofibrate layer and rosuvastatin layer, respectively, and wherein the test for fenofibrate is not less than 99.00% under storage conditions of 40°C temperature and 75% relative humidity after a period of 3 months.

In one embodiment, the present invention provides a multilayer pharmaceutical composition comprising a fixed dose combination of rosuvastatin or a pharmaceutically acceptable salt thereof and fenofibrate or a pharmaceutically acceptable salt thereof, wherein the fenofibrate or a pharmaceutically acceptable salt thereof itself and rosuvastatin or a pharmaceutically acceptable salt thereof are present in separate layers, and where fenofibrate and rosuvastatin are immediately released from the fenofibrate layer and rosuvastatin layer, respectively, and where the total amount of impurities related to fenofibrate is less than 0.100% under storage conditions of 40 °C temperature and 75% relative humidity after a period of time of 3 months.

In one embodiment, the present invention provides a multilayer pharmaceutical composition comprising a fixed dose combination of rosuvastatin or a pharmaceutically acceptable salt thereof and fenofibrate or a pharmaceutically acceptable salt thereof, wherein the fenofibrate or a pharmaceutically acceptable salt thereof itself and rosuvastatin or a pharmaceutically acceptable salt thereof are present in separate layers, and where fenofibrate and rosuvastatin are immediately released from the fenofibrate layer and rosuvastatin layer, respectively, and where the antiisomeric impurity of rosuvastatin is less than 0.250% under storage conditions of 40°C and 75% relative humidity after a period of 3 months.

In one embodiment, the present invention provides a multilayer pharmaceutical composition comprising a fixed dose combination of rosuvastatin or a pharmaceutically acceptable salt thereof and fenofibrate or a pharmaceutically acceptable salt thereof, wherein the fenofibrate or a pharmaceutically acceptable salt thereof itself and rosuvastatin or a pharmaceutically acceptable salt thereof are present in separate layers, and wherein fenofibrate and rosuvastatin are immediately released from the fenofibrate layer and rosuvastatin layer, respectively, and wherein the impurity Rosuvastatin -oxo is less than 0.300% under storage conditions of 40°C and 75% relative humidity after a period of 3 months.

In one embodiment, the present invention provides a multilayer pharmaceutical composition comprising a fixed dose combination of rosuvastatin or a pharmaceutically acceptable salt thereof and fenofibrate or a pharmaceutically acceptable salt thereof, wherein the fenofibrate or a pharmaceutically acceptable salt thereof itself and rosuvastatin or a pharmaceutically acceptable salt thereof are present in separate layers, and wherein fenofibrate and rosuvastatin are immediately released from the fenofibrate layer and rosuvastatin layer, respectively, and wherein the impurity of Rosuvastatin lactone is less than 0.150% under storage conditions of 40°C and 75% relative humidity after a period of 3 months.

In one embodiment, the present invention provides a multilayer pharmaceutical composition comprising a fixed dose combination of rosuvastatin or a pharmaceutically acceptable salt thereof and fenofibrate or a pharmaceutically acceptable salt thereof, wherein the fenofibrate or a pharmaceutically acceptable salt thereof itself and rosuvastatin or a pharmaceutically acceptable salt thereof are present in separate layers, and wherein fenofibrate and rosuvastatin are immediately released from the fenofibrate layer and rosuvastatin layer, respectively, and wherein the test for Rosuvastatin is not less than 99.00% under storage conditions of 40°C and 75% relative humidity after a period of 3 months.

In one embodiment, the present invention provides a multilayer pharmaceutical composition comprising a fixed dose combination of rosuvastatin or a pharmaceutically acceptable salt thereof and fenofibrate or a pharmaceutically acceptable salt thereof, wherein the fenofibrate or a pharmaceutically acceptable salt thereof itself and rosuvastatin or a pharmaceutically acceptable salt thereof are present in separate layers, and where fenofibrate and rosuvastatin are immediately released from the fenofibrate layer and rosuvastatin layer, respectively, and where the total amount of rosuvastatin-associated impurities is less than 0.700% under storage conditions of 40°C and 75% relative humidity after a period of 3 months.

In more detailed aspects, the present invention provides a multilayer pharmaceutical composition comprising a fixed dose combination of rosuvastatin or a pharmaceutically acceptable salt thereof and fenofibrate or a pharmaceutically acceptable salt thereof and suitable pharmaceutically acceptable excipients, wherein the excipients pharmaceutically acceptable are selected from one or more fillers or diluents, one or more binders, one or more disintegrants, one or more lubricants, one or more film coating agents, one or more pigments or plasticizers, and the like.

For the purposes of this specification, the term "immediate release" means a composition, component, layer, or unit comprising rosuvastatin and fenofibrate that releases rosuvastatin and fenofibrate from the composition, component, layer, or unit immediately, i.e., not according to a delayed or prolonged release mechanism The multilayer pharmaceutical composition according to the present invention provides immediate release of fenofibrate and rosuvastatin from the fenofibrate layer and the rosuvastatin layer, respectively.

Pharmaceutical excipients for use in the present invention are selected from one or more fillers, one or more diluents, one or more binders, one or more disintegrants, one or more lubricants, one or more glidants, one or more surfactants/wetting agents. , one or more film coating agents, one or more pigments or plasticizers, and the like.

In accordance with the present invention, fillers or diluents may include, but are not limited to, ammonium alginate, calcium carbonate, calcium lactate, calcium phosphate dibasic anhydrous, calcium phosphate dibasic dihydrate, calcium phosphate tribasic, calcium silicate, calcium sulfate, microcrystalline cellulose, powdered cellulose, silicified microcrystalline cellulose, cellulose acetate, maize starch and pregelatinized starch, dextrates, dextrin, dextrose, erythritol, ethylcellulose, fructose, fumaric acid, glyceryl palmitostearate, isomalt, kaolin, lactitol , lactose anhydrous, lactose monohydrate, lactose monohydrate and maize starch, lactose monohydrate and povidone, lactose monohydrate and spray-dried lactose, lactose monohydrate and microcrystalline cellulose, magnesium carbonate, magnesium oxide, maltitol, maltodextrin, maltose, mannitol, polydextrose , polymethacrylates, simethicone, sodium alginate, sodium chloride, sorbitol, starch, pregelatinized starch c, sterilizable corn starch, sucrose, compressible sugar, icing sugar, sugar spheres, b-cyclodextrin sulfobutyl ether, sunflower oil, talc, tragacanth, trehalose, xylitol, and mixtures thereof.

In accordance with the present invention, binders may include, but are not limited to, acacia, agar, alginic acid, calcium carbonate, calcium phosphate tribasic, calcium lactate, carbomer, sodium carboxymethylcellulose, carrageenan, cellulose acetate phthalate, ceratonia, microcrystalline cellulose, chitosan, copovidone, cottonseed oil, dextrates, dextrin, dextrose, ethylcellulose, gelatin, liquid glucose, glyceryl behenate, guar gum, hydroxyethylcellulose, hydroxyethylmethylcellulose, hydroxypropylcellulose, hydroxypropylstarch, anhydrous lactose, spray-dried lactose, hydroxypropylcellulose low substituted, hypromellose, inulin, lactose monohydrate, magnesium aluminum silicate, maltodextrin, maltose, methylcellulose, pectin, poloxamer, polycarbophil, polydextrose, polyethylene oxide, polymethacrylates, povidone, sodium alginate, pregelatinized starch, starch, sucrose, oil sunflower oil, hydrogenated vegetable oil, vitamin e, p succinate polyethylene glycol, zein, tragacanth, polyethylene glycol, polyvinylpyrrolidone, stearic acid, tricaprylin, and mixtures thereof.

In accordance with the present invention, disintegrants may include, but are not limited to, alginic acid, calcium alginate, calcium carboxymethylcellulose, sodium carboxymethylcellulose, cellulose, microcrystalline cellulose, powdered cellulose, chitosan, colloidal silicon dioxide, corn starch, and pregelatinized starch. , croscarmellose sodium, crospovidone, docusate sodium, glycine, guar gum, low substituted hydroxypropyl cellulose, hydroxypropyl starch, lactose monohydrate and corn starch, magnesium aluminum silicate, methyl cellulose, polacrilin potassium, povidone, sodium alginate, sodium starch glycolate, starch, pregelatinized starch and mixtures thereof.

In accordance with the present invention, lubricants may include, but are not limited to, calcium stearate, canola oil, hydrogenated castor oil, glyceryl behenate, glyceryl monostearate, glyceryl palmitostearate, lauric acid, leucine, magnesium stearate, oil Light mineral, mineral oil, magnesium lauryl sulfate, myristic acid, octyldodecanol, palmitic acid, poloxamer, polyethylene glycol, polyvinyl alcohol, potassium benzoate, sodium benzoate, sodium hyaluronate, sodium lauryl sulfate, sodium stearyl fumarate, lactose dried by spray, sterilizable corn starch, stearic acid, talc, tricaprylin, hydrogenated vegetable oil, zinc stearate, sodium chloride, and mixtures thereof.

According to the present invention, glidants may include, but are not limited to, calcium phosphate tribasic, powdered cellulose, colloidal silicon dioxide, hydrophobic colloidal silica, magnesium oxide, magnesium trisilicate, magnesium silicate, silicon dioxide, talc. and mixtures thereof.

According to the present invention, surfactants/wetting agents may include, but are not limited to, benzalkonium chloride, benzethonium chloride, cetylpyridinium chloride, docusate sodium, glycine, glycofurol, hypromellose, poloxamer, phospholipids, polyoxyethylene alkyl ethers, derivatives of polyoxyethylene castor oil, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene stearates, sodium lauryl sulfate, sorbitan esters (sorbitan fatty acid esters), tricaprylin, and mixtures thereof.

The dose and dosage ratio of rosuvastatin calcium and fenofibrate can be adapted based on various factors, such as symptoms, age, and body weight of the patients. According to the present invention, the dose of rosuvastatin calcium is usually 0.1 to 100 mg, in particular, 1 to 50 mg. More specifically, unit doses of rosuvastatin calcium for inclusion in a multilayer pharmaceutical composition of the present invention are 5, 10, or 20 mg.

According to the present invention, unit doses of the fenofibrate for use in the present invention may be 10 mg to 500 mg, preferably 50 mg to 350 mg. More particularly, the unit dosage concentration of fenofibrate for inclusion in a multilayer pharmaceutical composition of the present invention is 160 mg. According to the present invention, the multilayer pharmaceutical composition comprising a fixed dose combination can be administered once or twice a day to the patient.

In a more preferred aspect of the invention, the present invention provides a process for the preparation of a multilayer pharmaceutical composition comprising a fixed dose combination of rosuvastatin calcium, fenofibrate and one or more pharmaceutically acceptable excipients, which are described/exemplified in section present document.

In a particular preferred embodiment, the dosage form of the present invention is a solid dosage form such as a tablet, a capsule, a powder and a sachet, but preferably a tablet.

The pharmaceutical composition described herein can be prepared by conventional technology well known to those skilled in the art.

A typical bilayer tablet (rosuvastatin calcium and fenofibrate) of this invention comprises one or more fillers or diluents (such as lactose, microcrystalline cellulose), one or more binders (such as povidone, microcrystalline cellulose, lactose, etc.). .), one or more disintegrants (such as microcrystalline cellulose, croscarmellose sodium, colloidal silicon dioxide, crospovidone), one or more lubricants (such as magnesium stearate), one or more glidants (such as example, tribasic calcium phosphate, colloidal silicon dioxide and magnesium oxide) and/or one or more surfactants (such as sodium lauryl sulfate).

According to the present invention, a "multilayer pharmaceutical composition" is a multilayer tablet. The multilayer tablet can be, for example, a bilayer tablet.

According to the present invention, "bilayer tablet" means a tablet comprising rosuvastatin or a pharmaceutically acceptable salt thereof and fenofibrate, wherein rosuvastatin and fenofibrate are present in separate layers (i.e., rosuvastatin and fenofibrate are not mixed during the preparation of the composition). In accordance with the present invention, "wet granulation" involves the addition of a granulating fluid, typically water, which acts as a granulating liquid, to an agitated powder comprising the materials to be granulated.

In accordance with the present invention, "direct compression" involves a tableting process in which the dry ingredients are thoroughly mixed and then compressed into tablets.

According to the present invention, "dissolution" refers to the rate of drug release from a dosage form that can be measured by standardized methods.

According to the present invention, the expression "multilayer pharmaceutical composition" means a pharmaceutical composition having at least two layers. Examples of a multi-layer pharmaceutical composition are, but are not limited to: multi-layer tablets, such as bi-layer tablets, tri-layer tablets, multi-layer tablets, compressed granules, tablet-coated granules, multiple unit granule system (MUPS), tablet-in-tablet, tablet Capsule(s), compression-coated tablets and the like.

Next, the manufacturing process of the pharmaceutical composition of the present invention will be explained in detail:

EXAMPLES

To better illustrate the present invention, the following examples are provided for ease of understanding. However, it is not intended to limit the scope of the present invention in any way and it is readily apparent to those skilled in the art, in light of the teachings of this invention, that certain changes and modifications may be made without departing from the scope of the present invention. invention.

Preparation of fenofibrate (micronized):

For Comparative Example 1 and Examples 2-4 the fenofibrate has been micronized to have a particle distribution characterized by the DTP parameters listed in Table 1 below.

Table 1: Micronized fenofibrate particle size distribution parameters, where NMD stands for "not more than"

Comparative example 1: monolayer tablets of rosuvastatin and fenofibrate (not according to the invention)

Table 2: Composition of a conventional rosuvastatin/fenofibrate monolayer tablet with a dose of min 1 mm rimi

continuation

Manufacturing procedure:

Fenofibrate granules were prepared by a wet granulation process using the principles listed above under serial numbers 1 through 9. Rosuvastatin combination was prepared by mixing rosuvastatin calcium with microcrystalline cellulose, crospovidone, colloidal anhydrous silica, and light magnesium oxide. . Subsequently, the fenofibrate granules and the rosuvastatin combination were mixed homogeneously. Sodium stearyl fumarate was added to the fenofibrate granule mixture and the combination of rosuvastatin and lubricated mixture was compressed using suitable tools with a monolayer compression machine. The obtained monolayer tablet was film-coated using Opadry.

Example 2: Rosuvastatin and fenofibrate bilayer tablets (according to the present invention)

Table 3: Weight ratios of ingredients in two layers of the rosuvastatin/fenofibrate multilayer tablet of the invention. The multilayer tablet of the invention is available, for example, in a combined dose of 5+160 mm rimi 1 1 mm rimi 2 1 mm rimi .

continuation

Manufacturing procedure:

The manufacturing procedure is the same as that described below in Example 3:

Example 3: Bilayer tablets of rosuvastatin and fenofibrate (according to the present invention)

Table 4: Absolute amounts of ingredients in two layers of rosuvastatin/fenofibrate multilayer tablets of the invention at different doses.

** - Not present in the final composition

*- 5.21/10.42/20.84 mg rosuvastatin calcium is equivalent to 5/10/20 mg rosuvastatin.

Manufacturing procedure:

Layer-1 (fenofibrate layer):

A fenofibrate mixture was prepared by sieving the intragranular ingredients listed above under serial numbers 1 to 7 through a suitable sieve and loading into a suitable granulator. A binder solution was prepared by dissolving povidone (serial #8) in purified water adding isopropyl alcohol to obtain a suitable mix. The fenofibrate granules were obtained by granulating the fenofibrate mixture (serial #1-7) with the granulating solvent in the appropriate granulator. Subsequently, the obtained granules and the extragranular principles listed above with serial numbers 11 to 14 were mixed homogeneously. Finally, sodium stearyl fumarate (serial no. 15) was added to the mixture to obtain a lubricated fenofibrate layered mixture.

Layer-2 (Rosuvastatin layer):

A rosuvastatin mixture was prepared by mixing rosuvastatin calcium, anhydrous lactose, microcrystalline cellulose, crospovidone, and light magnesium oxide in a blender. The sieved magnesium stearate was mixed with the previously prepared rosuvastatin mixture to obtain a lubricated mixture.

Bilayer tablet:

The lubricated mixtures of fenofibrate and rosuvastatin were compressed using suitable tools with a bilayer compression machine. The obtained bilayer tablet was film-coated using Opadry.

Dissolution study:

Dissolution studies were performed for:

- Innovative sample of fenofibrate (Supralip®), a 160 mg film-coated tablet

- Comparative Example 1, monolayer tablet, not according to the invention

- Example 3a, bilayer tablet, according to the invention

Dissolution studies were performed using the following parameters:

Medium: 0.05 M SLS in water, Apparatus: Paddle type, Volume: 1000 ml, Speed: 50 RPM (Revolutions per minute) The dissolution profile results obtained from fenofibrate are shown in the following Table 5.

T l : R lliilinfn fi rlml

The above dissolution data provide evidence that the dissolution of fenofibrate after 60 minutes is at least 20% higher for the micronized fenofibrate bilayer tablet than for the monolayer tablet of Comparative Example 1. Therefore, the present invention allows to provide a multilayer tablet, a pharmaceutical composition comprising a fixed dose combination of rosuvastatin calcium and fenofibrate having a greater dissolution of fenofibrate after 60 minutes than conventional monolayer compositions.

Example 4: Rosuvastatin and fenofibrate bilayer tablets (according to the present invention)

manufacturing process

The manufacturing procedure is similar to that described in Example 3:

Dissolution Study: Dissolution studies were carried out using the same parameters provided above in Example 3.

T l : R l l i i l in f nfi r l ml 4 ml 4.

Stability study:

The stability study was carried out for bilayer tablets obtained in example 4a, example 4b and example 4c at a temperature of 40 °C and 75% relative humidity for periods of time of 1 month, 2 months and 3 months. The results of the stability study obtained are shown in Table 7a and Table 7b below.

From the stability data provided in Table 7a and Table 7b, it can be concluded that the multilayer pharmaceutical composition comprising a fixed dose combination of the present invention is stable.

Example 5 : Bioavailability test (according to the present invention)

The bioavailability of the fixed dose combination according to the present invention, in the form of bilayer tablets of rosuvastatin and fenofibrate, was studied.

Study design

The bioequivalence study was carried out according to existing European Medicines Agency bioequivalence guidelines.

samples

The samples used in the bioavailability test are the following:

a) Test sample: The fixed-dose combination according to the present invention, in the form of a bilayer tablet of rosuvastatin and 4c-fenofibrate.

b) Reference sample: SECALIP SUPRA® 160 mg tablet and CRESTOR® 20 mg tablet.

Determinations

The procedure involved measurement of the plasma concentration of fenofibric acid, the active metabolite of fenofibrate and rosuvastatin, for 96 hours at predetermined time points.

The mean plasma concentrations of the metabolite fenofibric acid and rosuvastatin were determined. The values of fenofibric acid concentration and rosuvastatin concentration after once daily administration of the test sample of the present invention are summarized in Table 8. In addition, the values of fenofibric acid concentration and rosuvastatin concentration after once daily administration of the reference sample are also shown in Table 8. In addition, the plasma concentration-time profile after once daily administration of the test sample of the invention is shown for fenofibric acid and rosuvastatin, respectively, in Figure 1 and Figure 2.

Table 8

In addition, the main pharmacokinetic parameters exhibited after once-daily administration of the fixed-dose combination according to the present invention in the form of a rosuvastatin-fenofibrate bilayer tablet from Example 4c and once-daily administration of the products of rosuvastatin and fenofibrate were measured. reference sample (S ^e C ^a LIP S ^u PRA® 160 mg tablet and ^c R ^e STOR® 20 mg tablet) by LC-MS/M ^s method. In particular, the values of Cmax, Tmax, AUC, t12, (half-life) and Az (elimination rate constant), as well as the standard deviation (SD) of the test sample and the reference sample, are summarized in Table 9.

Table 9

The above pharmacokinetic parameters and the mean plasma concentration values of the metabolite fenofibric acid and rosuvastatin shown in the above tables surprisingly demonstrated that once daily administration of the fixed dose combination according to the present invention, in the form of tablets rosuvastatin and fenofibrate bilayer of Example 4c, is bioequivalent to the total drug exposure obtained after once-daily administration of the concomitant intake of one SECALIP SUPRA® 160 mg tablet and one CRESTOR® 20 mg tablet. This means that the fixed-dose combination according to the present invention has comparable bioavailability, because the rate and extent to which the fenofibric acid metabolite, as well as rosuvastatin, are absorbed from the fixed-dose combination according to the present invention and become available at the site of drug action are the same as with concomitant intake of reference samples. Therefore, once-daily administration of the fixed-dose combination according to the present invention can be considered equivalent to once-daily administration of the immediate-release reference sample, i.e., concomitant intake of one 160 mg tablet. of SECALIP SUPRA® and a 20 mg tablet of CRESTOR®.

In conclusion, the multilayer pharmaceutical composition of the invention that comprises a fixed-dose combination of rosuvastatin and fenofibrate, according to example 4c, represents a significant improvement over the corresponding SECALIP SUPRA® and CRESTOR® monotherapies, since it provides the two active ingredients. into a single tablet for once-daily treatment, thus reducing the patient's pill burden. Therefore, the fixed-dose combination is suitable for patients with mixed dyslipidemia who currently need to take the two monotherapies separately, thus meeting an unmet medical need and providing an improvement in ensuring compliance and adherence to treatment. .

Claims (9)

1. Multilayer pharmaceutical composition comprising a fixed dose combination of rosuvastatin or a pharmaceutically acceptable salt thereof and fenofibrate or a pharmaceutically acceptable salt thereof, wherein the fenofibrate or a pharmaceutically acceptable salt and rosuvastatin or a pharmaceutically acceptable salt are present in separate layers, namely a fenofibrate layer and a rosuvastatin layer, and wherein the fenofibrate layer comprises micronized fenofibrate, and wherein fenofibrate and rosuvastatin are immediately released from the fenofibrate layer and rosuvastatin layer, respectively. 2. Multilayer pharmaceutical composition according to claim 1, characterized in that the micronized fenofibrate has a mean volumetric diameter D(v, 50) greater than 0.02 pm and less than or equal to 20 pm, preferably greater than 0.04 pm and less or equal to 10 pm, more preferably greater than 0.05 pm and less than or equal to 7 pm, even more preferably greater than 0.05 pm and less than or equal to 5 pm, more preferably greater than 0.05 pm and less than or equal to 4 p.m. 3. Multilayer pharmaceutical composition according to any one of claims 1-2, characterized in that the micronized fenofibrate has a particle size distribution (DTP) in which D(v,10) is greater than 0.02 pm and less than or equal to 7 pm, preferably greater than 0.04 pm and less than or equal to 5 pm, more preferably greater than 0.04 pm and less than or equal to 4 pm, even more preferably greater than 0.05 pm and less than or equal to 3 pm, even more preferably greater than 0.05 pm and less than or equal to 2 pm; and/or D(v,50) is greater than 0.04 pm and less than or equal to 20 pm, preferably greater than 0.08 pm and less than or equal to 10 pm, more preferably greater than 0.1 pm and less than or equal to 7 pm, even more preferably greater than 0.1 pm and less than or equal to 5 pm, even more preferably greater than 0.1 pm and less than or equal to 4 pm; and/or D(v,90) is greater than 0.05 pm and less than or equal to 47 pm, preferably greater than 0.1 pm and less than or equal to 25 pm, more preferably greater than 0.2 pm and less than or equal to 18 pm, even more preferably greater than 0.4 pm and less than or equal to 13 pm, even more preferably greater than 0.5 pm and less than or equal to 10 pm; and the width of the particle size distribution (DTP), expressed as a range, is between 1.2 and 3, preferably between 1.3 and 2.5, more preferably between 1.6 and 2.3. 4. Multilayer pharmaceutical composition according to any one of claims 1-3, characterized in that the fenofibrate is not in the form of a solid solution or solid dispersion. 5. Multilayer pharmaceutical composition according to any one of claims 1-4, characterized in that the fenofibrate layer comprises less than 20% w/w or is free of one or more excipients or vehicles with a melting point below 75 °C, preferably less than 80°C, more preferably less than 90°C, even more preferably less than 100°C. 6. Multilayer pharmaceutical composition according to claim 5, characterized in that one or more excipients or vehicles are selected from a group consisting of polyethylene glycols, polypropylene glycols, polyoxyethylenes, polyoxypropylenes, poloxamers, straight-chain saturated hydrocarbons, sorbitan esters, paraffins, fats , oils and mixtures thereof. 7. Multilayer pharmaceutical composition according to any one of claims 1 to 6, wherein rosuvastatin or a pharmaceutically acceptable salt thereof is present in an amount of 5 mg to 20 mg, and fenofibrate or a pharmaceutically acceptable salt thereof. it is present in an amount of 140 mg to 180 mg and rosuvastatin and fenofibrate are not mixed. The pharmaceutical composition according to claim 7, wherein the pharmaceutical composition is a bilayer tablet, wherein said bilayer tablet comprises 5 to 20 mg rosuvastatin or a pharmaceutically acceptable salt thereof and 160 mg fenofibrate. 9. Process for preparing a pharmaceutical composition according to one of the preceding claims comprising the following steps: a) prepare a mixture of fenofibrate layers lubricated by Yo. preparing a fenofibrate mixture by subjecting micronized fenofibrate, lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, crospovidone, ferric oxide red, and sodium lauryl sulfate to a granulation process; ii. preparing a binder solution by dissolving povidone in purified water and adding isopropyl alcohol iii. granulating the mixture of fenofibrate obtained in step i) and the binder solution obtained in step ii) and drying the granules in a suitable dryer; iv. the addition of microcrystalline cellulose, crospovidone, croscarmellose sodium and colloidal anhydrous silica in extragranular form to the granules obtained in step iii) v. lubrication of the dry granules with sodium stearfumarate; b) prepare a mixture of layers of rosuvastatin lubricated by Yo. preparing a rosuvastatin mixture by mixing rosuvastatin calcium, lactose anhydrous, microcrystalline cellulose, crospovidone, and light magnesium oxide in a blender; ii. the sieved magnesium stearate mixture with the rosuvastatin mixture; Y c) compressing the lubricated fenofibrate layer mixture and the lubricated rosuvastatin layer mixture using a multi-layer compression machine.